Topical microbicides are defined as vaginally applied products that prevent male-to-female or female-to-male HIV transmission. The high error rate of the HIV reverse transcriptase (RT) drives the development of resistance and genomic diversity in HIV. The current pan-resistance to all classes of HIV inhibitors, such as those found in O group virus for non-nucleoside RT and protease (PR) inhibitors, raises an important question with regard to the development of microbicides targeting RT or PR. These concerns may be extended to inhibitors of HIV entry due to rapid emergence of mutations in the envelope (Env) glycoprotein under selective pressure. There is thus an urgent need to identify new anti-HIV compounds, which target viral components other than PR, RT and Env, and which may be developed as safe and effective microbicides. We identified a short linear peptide called Virocide, which neutralizes HIV at an nM range. Several lines of evidence s cells even when applied twice daily to cells at a concentration 20-200-fold superior to that which blocks HIV infection; iii) Virocide does not harm mice injected i.v. twice daily with high peptide concentrations (0.5 mg) for a period of 3 days; and iv) Virocide apparently does not create lesions in the vaginal epithelium of humanized mice since the peptide, rather than promoting transmission, completely blocks intravaginal transmission. Virocide represents an attractive microbicide candidate for several reasons: i) Virocide inhibits infection of a broad range of primary isolates in various primary human cell types; ii) it interferes with the three mechanisms involved in HIV transmission: genital epithelial transmigration, dendritic cell-mediated transmission, and infection of mucosal target cells; iii) Virocide is extremely efficacious since less than 15 min of exposure suffices to neutralize HIV; iv) it is potent for two hours both prior to and after addition of HIV to cells, suggze the anti-HIV efficacy of Virocide in vitro as well as its toxicity and immunogenicity in vivo. If these studies unambiguously demonstrate that Virocide represents an attractive anti-HIV microbicide candidate, we will be in a position to test its efficacy as a topical microbicide in vivo. [unreadable] [unreadable] PUBLIC HEALTH RELEVANCE: The goal of this project is to conduct in vitro and in vivo studies designed to support the preclinical development of a short peptide as a novel anti-HIV microbicide candidate. There is an urgent need for the development of safe, effective topical microbicides to prevent the sexual transmission of HIV and to allow the female partner to take personal responsibility for use and application. The development of a safe, effective acceptable topical microbicide to prevent the sexual transmission of HIV-1 could play a major role in worldwide reduction of the over 14,000 new HIV-1 infections per day, and potentially save millions of lives. 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